Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis

Background

In patients with diabetes type 2 (T2DM), sodium-glucose cotransporter-2 (SGLT2) inhibitors positively influence certain intermediate markers of vascular risk (e.g. glucose concentrations, weight, albuminuria, blood pressure), but on the other hand they may cause LDL-C increase, genito-urinary infections, metabolic acidosis and bone fracture [1-5]. Currently there is uncertainty about the effects of SGLT2 inhibitors on clinical outcomes and it is not clear whether there are differences between various SGLT2 inhibitors.
In this systematic review and meta-analysis, the evidence from relevant randomised trials and regulatory submissions regarding major clinical efficacy and safety outcomes was evaluated in adults with T2DM, both overall, as well as separately for individuals SGLT2 inhibitors. The review included data from 57 trials including 33,385 participants, who were exposed to seven different SGLT2 inhibitors, and from six regulatory submissions that provided data for 37,525 individuals.

Main results

SGLT2 inhibitors protected against the risk of:

major adverse CV events: RR: 0.84; 95% CI: 0.75–0.95; P = 0.006

CV death: RR: 0.63; 95% CI: 0.51–0.77; P < 0.0001

Heart failure: RR: 0.65; 95% CI: 0.50–0.85; P = 0.002

death from any cause: RR: 0.71; 95% CI: 0.61–0.83; P < 0.0001

No clear effect was apparent from the use of SGLT2 inhibitors on:

non-fatal MI: RR: 0.88; 95% CI: 0.72–1.07; P = 0.18

angina: RR: 0.95; 95% CI: 0.73–1.23; P = 0.70

The use of SGLT2 inhibitors increased the risk of non-fatal stroke: RR: 1.30; 95% CI: 1.00–1.68; P = 0.049.
There was no clear evidence about different effects of individual SGLT2 inhibitors on CV outcomes or death (all I2< 43%), but it should be noted that efficacy results were mainly driven by the EMPA-REG OUTCOME trial with empagliflozin.

Use of SGLT2 inhibitors led to an increased risk of genital infections. Concerning other safety outcomes, different definitions and approaches of reporting were used, depending on the SGLT2 inhibitor and the source of the data, making analysis of adverse events difficult (see article for details).

Conclusion

In patients with T2DM at high risk for CV events, the currently available data provide evidence supporting the clinical benefit of SGLT2 inhibitors and their protective effects against MACE, with the exception of non-fatal stroke. Data on adverse effects of this drug class are less clear, and need further elucidation.